PROJECT SUMMARY Gastric cancer is the second leading cause of cancer-related death worldwide. The loss of parietal cells (oxyntic atrophy) is a critical step in the pathogenesis of chronic gastritis and gastric cancer. Nevertheless, the mechanisms that mediate the metaplastic response to the loss of parietal cells and the steps leading to the development of cancer within the atrophic gastric mucosa remain obscure. The loss of parietal cells in humans leads to the development of two identifiable metaplasias: intestinal metaplasia (the presence of intestinal goblet cells in the gastric mucosa) and spasmolytic polypeptide expressing metaplasia or SPEM (the presence of antral type mucous cells in the fundus). In contrast with humans, rodents only develop SPEM in response to either chronic oxyntic atrophy in H. felis infected mice or in mice with acute oxyntic atrophy induced by the parietal cell protonophore DMP-777. We have investigated the factors that lead to the development of SPEM in the face of oxyntic atrophy. These studies indicate that SPEM is the precursor lesion for dysplasia and neoplasia in H. felis infected mice. Using DMP777, we have defined the dynamics of the induction of SPEM in rodents and these studies support the hypothesis that SPEM develops from transdifferentiation of chief cells. Since the loss of parietal cells is a requisite step for the development gastric adenocarcinoma, we will seek to define the process of SPEM induction in both acute and chronic models of SPEM induction. First, we will define the origin of SPEM and the roles of the intramucosal factor amphiregulin in the regulation of the emergence SPEM following loss of parietal cells. Second, we will examine the differences and commonalities between SPEM lineages observed after DMP777 treatment and after H. felis infection. Third, we will determine utility of murine SPEM- related transcripts and proteins as biomarkers for gastric pre-neoplasia in humans. These studies should lead to critical insights into the metaplastic response in the face of oxyntic atrophy as well as to the identification of biomarkers for pre-neoplasia applicable to the screening of populations at risk for developing gastric cancer. NARRATIVE Gastric cancer, the second leading cause of cancer related death worldwide, develops from pre-cancerous changes in the cells lining the stomach. The studies proposed here will utilize animal models to understand the pre-cancerous process and to define possible biomarkers that could be used for screening in humans for risk of gastric cancer.